title: ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling.
abstract: α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to "slowing" of the metabolic and physiological properties of fast fibers. Here, we have shown that α-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-actinin-3-deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-actinins play a role in the regulation of calcineurin signaling.
authors.forename: Jane T
authors.initials: JT
authors.lastname: Seto
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.forename: Xi Fiona
authors.initials: XF
authors.lastname: Zheng
authors.forename: Fleur
authors.initials: F
authors.lastname: Garton
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Hogarth
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houweling
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000222:Adaptation, Physiological; D000328:Adult; D000368:Aged; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000502:physiology*; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D011485:Protein Binding
chemical_list: C118456:ACTN3 protein, human; D002352:Carrier Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C523647:Myoz1 protein, mouse; D000185:Actinin; D019703:Calcineurin